The present invention relates to a polyol, a method of producing it, and use thereof. More particularly, the invention relates to a bioactive compound of use as a medicine, for example as a prophylactic and therapeutic drug for diseases such as gastric ulcer and duodenal ulcer, and an anti-Helicobacter pylori (hereinafter may be referred to as H. pylori or HP) agent comprising said compound.
Being a member of the group of bacteria doing harm in the gastrointestinal tract, Helicobacter pylori is a gram-negative microaerophile belonging to the genus Helicobacter and, as suggested, may be a major factor in the recurrences of gastritis, duodenal ulcer and stomach ulcer.
For the treatment of various diseases associated with Helicobacter pylori infection, chemotherapy such as a two-drug combined therapy using a bismuth drug and an antibiotic or a three-drug combined therapy using a bismuth drug, metronidazole (U.S. Pat. No. 2,944,061), and either tetracycline (e.g. U.S. Pat. No. 2,712,517) or amoxicillin (U.S. Pat. No. 3,192,198) is being practiced today. The ternary therapy consisting of a gastric proton pump inhibitor, amoxicillin, and clarithromycin has also been found to be effective (Gut, 1995, 37 (Supplement 1): A365) (Gastroenterology, 1996, 110: A171). Such drugs as bismuth drugs, antibiotics, and metronidazole are all administered by the oral route.
Referring to polyols, PCT International Patent Application Publication No. WO93/06838 and Acta Chemical Scandinavica B 36, 515-518 (1982) disclose 
respectively, as synthetic intermediates, and Carbohyd. Res., 28 (2), 263-280 (1973) states that 
is active against gram-negative bacteria.
For an improved expression of the efficacy of an active ingredient and a reduced risk for side effects, an attempt was made to formulate amoxicillin, for instance, into a gastric mucosa-adhesive composition to prolong its intragastric residence time and let amoxicillin be released at a controlled rate and with consequent improved availability of active ingredients (WO 94/00112). It has been demonstrated that the rate of clearance of Helicobacter pylori can be improved by causing an anti-Helicobacter pylori substance to stay in the stomach longer to ensure prolonged exposure of the bacteria to the active substance [Scand. J. Gastroenterol., 29, 16-42 (1994)].
However, in order that a sufficient growth-inhibitory concentration may be maintained in the habitat of Helicobacter pylori, said bismuth drugs, antibiotics, or metronidazole must be administered daily in massive doses and such therapeutics entail various troubles, for example, the onset of adverse reactions such as vomiting and diarrhea. Under the circumstances, the present invention has for its object to provide a novel medicinal agent having high antibacterial activity, particularly against Helicobacter pylori and other bacteria of the genus Helicobacter, and producing clinically rewarding prophylactic and therapeutic responses with a reduced incidence of adverse reactions.
Under the circumstances, the present invention has for its object to provide a novel medicinal agent having high antibacterial activity, particularly against Helicobacter pylori and other bacteria of the genus Helicobacter, and producing clinically rewarding prophylactic and therapeutic responses with a reduced incidence of adverse reactions.
The present invention has for its object to provide a pharmaceutical composition which has enhanced mucosa-adherent activity compared with other gastric mucosa-adherent preparations, and consequently, an extremely improved efficacy of the active ingredient, in particular, an anti-Helicobacter pylori composition and a pharmaceutical preparation, for the prophylaxis, treatment or prevention of relapse of gastroduodenal ulcers, which is very satisfactory and favorable in having anti-Helicobacter pylori effect, low risk for side effects, sustained effect, and safety.
As the result of their intensive research, the inventors of the present invention synthesized a novel polyhydric alcohol (polyol) of the following general formula 
[wherein R1 represents amino which may be substituted; R2 represents carboxy which may be esterified or amidated; R3, R4, R5, and R6 each represent hydroxy which may be protected; Q represents aryl which may be substituted], which is structurally distinct in that the following defined group: 
[Q and R2 are the same meaning as defined above] is directly bound to a carbon atom, and discovered that, because of this unique chemical structure, the above compound displays remarkable inhibitory activity against the bacteria doing harm in the gastrointestinal tract, particularly high anti-Helicobacter activity, with clinically favorable pharmacological characteristics such as a low risk for adverse effects. The present invention has been developed on the basis of the above finding.
In view of the above state of the art, the inventors of the present invention have discovered that the effectiveness of active ingredients (e.g. anti Helicobacter pylori effect) can be potentiated by incorporating an agent (e.g. a curdlan and/or a low-substituted hydroxypropylcellulose) which swells a viscogenic agent, in the objective gastric mucosa adhesive composition containing an active ingredient (e.g. anti Helicobacter pylori substance), and that the composition has favorable safety characteristics and an enhanced adhesion to the mucosa.
The present invention, therefore, relates to:
(1) a compound of the formula (I): 
xe2x80x83wherein R1 represents amino which may be substituted; R2 represents carboxy which may be esterified or amidated; R3, R4, R5, and R6 each represent hydroxy which may be protected; Q represents aryl which may be substituted; or a salt thereof,
(2) the compound according to (1), wherein R1 is an acylamino group or an amino group substituted by a hydrocarbon group which may be substituted,
(3) the compound according to (2), wherein the acylamino group is an amino group substituted by an amino acid residue,
(4) the compound according to (3), wherein the amino acid residue is an xcex1-amino acid residue,
(5) the compound according to (1), wherein R1 is an amino group or a group represented by the formula: 
xe2x80x83wherein R7 is an amino which may be substituted with a xcex1-L-amino acid residue which may be substituted with a xcex1-L-amino acid residue, R8 is a hydrocarbon group which may be substituted; R2 represents a carboxy group; R3, R4, R5, and R6 each represents a hydroxy group; Q represents a phenyl group,
(6) the compound according to (5), which is represented by the formula (V): 
xe2x80x83wherein R7 and R8 are of the same meaning as defined in (5),
(7) the compound according to (5), wherein R8 is a C1-10 alkyl group, a C6-14 aryl-C1-6 alkyl group, a C2-10 alkenyl group or a C2-10 alkynyl group, each of which may be substituted,
(8) the compound according to (7), wherein R8 is a C1-6 alkyl group or a C2-6 alkenyl group,
(9) the compound according to (7), wherein R7 is an amino group which may be substituted with a valyl group, a valylvalyl group, a valylisoleucyl group or a valylleucyl group,
(10) the compound according to (8), wherein R8 is an isobutyl group or an allyl group,
(11) the compound according to (1), wherein R1 is an amino group,
(12) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-valyl-L-valyl-L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid,
(13) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-valyl-L-isoleucyl-L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid,
(14) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-valyl-L-leucyl-L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid,
(15) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-valyl-L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid,
(16) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid,
(17) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-5-((S)-2-amino-4-pentenoyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionic acid,
(18) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-5-((S)-2-aminobutyryl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionic acid,
(19) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-isoleucyl-L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid,
(20) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-methionyl-L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid,
(21) a compound according to (1), which is (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-((S)-2-(L-norvalyl)amino-4-pentenoyl)aminohexanoyl]amino-3-phenylpropionic acid,
(22) a pharmaceutical composition comprising the compound according to (1),
(23) the composition according to (22), which is an anti-Helicobacter pylori agent,
(24) the Helicobacter pylori agent according to (23), which is a prophylactic and therapeutic drug for a disease associated with Helicobacter pylori infection,
(25) the Helicobacter pylori agent according to (24), wherein the disease associated with Helicobacter pylori infection is gastric or duodenal ulcer, gastritis, gastric cancer or gastric MALT lymphoma,
(26) a Helicobacter pylori agent comprising a combination of the compound according to (1) and at least one other antibacterial or/and antiulcerative agent,
(27) the composition according to (22), which is a gastric mucosa adhesive pharmaceutical composition,
(28) the composition according to (27), which comprises (a) the compound according to (1), (b) a lipid and/or a polyglycerol fatty acid ester and (c) a viscogenic agent capable of being viscous with water,
(29) the composition according to (28), wherein (c) the viscogenic agent is an acrylic polymer or a salt thereof,
(30) the composition according to (28), which comprises (d) a material which swells the viscogenic agent,
(31) the composition according to (30), wherein the material which swells the viscogenic agent is a curdlan and/or a low-substituted hydroxypropylcellulose,
(32) a method of producing the compound according to (1), which comprises reacting a carboxylic acid of the formula (II): 
xe2x80x83wherein R1 represents an amino which may be substituted; R3, R4, R5, and R6 each represent a hydroxy group which may be protected, or a salt thereof, or a reactive derivative thereof; with a compound of the formula (III): 
xe2x80x83wherein R2 represents a carboxy group which may be esterified or amidated; Q represents an aryl group which may be substituted, or a salt thereof,
(33) a method of producing the compound according to (1), which comprises reacting a compound of the formula (IV): 
xe2x80x83wherein R2 represents a carboxyl group which may be esterified or amidated; R3, R4, R5, and R6 each represent a hydroxy group which may be protected, Q represents an aryl group which may be substituted, or a salt thereof, or a reactive derivative thereof; with a compound of the formula: R9-X wherein R9 represents an acyl group, or hydrocarbon group which may be substituted; X represents a leaving group or a salt thereof, or a reactive derivative thereof,
(34) a method of producing the compound according to (5), which comprises growing a strain of microorganism of the genus Bacillus which is capable of producing the compound according to (5) in a culture medium to let the strain produce and accumulate the compound in the fermentation broth and harvesting the same,
(35) the method according to (34), wherein the strain of microorganism is Bacillus sp. HC-70 or Bacillus insolitus HC-72,
(36) Bacillus sp. HC-70 or Bacillus insolitus HC-72 which is capable of producing the compound according to (5),
(37) a method for prevention or treatment of a disease associated with Helicobacter pylori infection in a mammal which comprises administering to the mammal in need an effective amount of a compound of the formula (I): 
xe2x80x83wherein R1 represents amino which may be substituted; R2 represents carboxy which may be esterified or amidated, R3, R4, R5, and R6 each represents hydroxy which may be protected; Q represents aryl which may be substituted; or a salt thereof, and
(38) use of a compound of the formula (I): 
xe2x80x83wherein R1 represents amino which may be substituted; R2 represents carboxy which may be esterified or amidated; R3, R4, R5, and R6 each represents hydroxy which may be protected; Q represents aryl which may be substituted; or a salt thereof, for the preparation of an anti-Helicobacter pylori agent.